Many pharmaceutical solids can exist in different physical forms. Polymorphism is often defined as the ability of a compound to exist in at least two crystalline phases, where each crystalline phase has a different arrangement and/or conformation of molecules in a crystalline lattice. Non-crystalline solids consist of disordered arrangements of molecules, and do not possess a distinguishable crystal lattice.
The non-crystalline and different polymorphic forms of a pharmaceutical solid differ in internal solid state structure, and, thus, typically have different chemical and physical properties, including packing, thermodynamic, spectroscopic, kinetic, interfacial, solubility, reactivity, and mechanical properties. Those properties can have a direct impact on the quality and/or performance of a drug product, including its stability, dissolution rate, and bioavailability.
For example, until recently, the original crystalline form of aspirin, known as Form I, was the only known crystalline form of aspirin and the only form of aspirin that is stable at room temperature. However, as reported in Chemical & Engineering News, Nov. 21, 2005, Zaworotko et al., J. Am. Chem. Soc., 2005, 127, 16802, reported the synthesis of a second polymorphic form of aspirin. Aspirin Form II is kinetically stable at 100 K (−173° C.), but converts back to Form I at ambient conditions.
Amorphous glass aspirin has also been formed. However, except, possibly, for some microscopic residues, amorphous aspirin has been produced only at very low temperatures. Above the glass transition temperature of about 243 Kelvin (−30° C.), amorphous aspirin converts rapidly to the crystalline Form I. Thus, all prior art forms of aspirin convert to Form I at room temperature. As a result of the low temperature required to create and maintain the amorphous form, there has been essentially no practical application of the amorphous solid state form.
Johari et al., Physical Chemistry Chemical Physics, 2000, 2, 5479-5484, also report the vitrification of aspirin by melting and cooling and by ball-milling at ambient temperature to form a vitreous or supercooled viscous liquid aspirin that is stable against crystallization for several days at 298K. The viscous liquid was found to flow slowly when tilted in a container, but did not crystallize for four to five days at 298K. The vitreous aspirin samples did ultimately undergo complete crystallization, which was accelerated when the samples were kept at about 340K.
Johari et al. report that the vitreous state has a higher energy state than the crystal state with a lower frequency of its phonon modes and a greater anharmonicity that make absorption and assimilation directly from the solid state more effective and efficient. In its bulk form, the vitreous aspirin is reported to dissolve more slowly than the same mass of finely powdered crystals of aspirin. As is well known in the art, a bulk sample of a substance has a significantly smaller surface area than finely powdered crystals. That makes the dissolution of the bulk form much more difficult, accounting for the slower dissolution rate of the bulk vitreous aspirin reported by Johari et al.
The most stable form of a drug substance is often used in a formulation, as it has the lowest potential for conversion from one form to another. However, a different form that is sufficiently stable under the predicted storage conditions can be chosen to enhance the bioavailability of the drug product. The other form may be a metastable polymorph, i.e., a polymorphic form that is less stable than the most stable form, but typically does not convert to a different form during normal storage, or a non-crystalline form. A non-crystalline form lacks the regular molecular organization of a crystalline form, and does not need to lose crystal structure during dissolution in gastric juices. Therefore, non-crystalline forms often dissolve more quickly, and have a greater bioavailability than crystalline forms.
Although a non-crystalline form may be desirable for a pharmaceutical composition, the preparation of non-crystalline forms on an industrial scale is often problematic. Processes for the preparation of non-crystalline forms of pharmaceutical compositions include solidification of melt, reduction of particle size, spray-drying, lyophilization (also known as freeze-drying), removal of a solvent from crystalline structure, precipitation of acids and bases by a change in pH, and other such techniques.
Such processes are often unsuitable or impractical for production on an industrial scale. For example, to obtain a non-crystalline active pharmaceutical ingredient by solidification of melt, the active pharmaceutical ingredient has to be heated beyond its melting point, requiring the expenditure of a significant amount of energy, particularly when the active pharmaceutical ingredient has a high specific heat and/or heat of fusion. In addition, the melting the pharmaceutical composition may chemically alter the active pharmaceutical ingredient. Some materials also decompose before melting, and, thus, solidification of melt cannot be used.
Lyophilization is quite expensive on a large scale, and generally has limited capacity. Where the solvent is organic, lyophilization often presents a disposal and/or fire hazard.
Spray-drying requires dispersing a liquid solution in a volume of a heated gas sufficient to evaporate the solvent, leaving particulates of the solute. The heated gas is typically hot air or nitrogen. Spray drying, is typically limited to aqueous solutions unless special expensive safety measures are taken. In addition, contact of the pharmaceutical composition with the heated gas can result in degradation of the composition.
The form of a solid chemical compound, whether non-crystalline or crystalline, affects many of the properties of the compound that are important to the formulation of a pharmaceutical composition. The flowability of a milled solid is particularly important in the preparation of a pharmaceutical product, as flowability affects the ease with which a pharmaceutical composition is handled during processing. When a powdered compound does not flow freely, it may be necessary to use one or more glidants in a tablet or capsule formulation. Glidants used in pharmaceutical compositions include colloidal silicon dioxide, talc, starch, or tribasic calcium phosphate.
Another important property of a pharmaceutical compound that may depend on crystallinity is its dissolution rate in an aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences, as the dissolution rate imposes an upper limit on the rate at which an orally-administered active ingredient can reach the bloodstream of a patient. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
The discovery of new non-crystalline and crystalline forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.